Journal of Dispersion Science and Technology

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Preparation and Application of Nanoemulsions in

the Last Decade (2000–2010)

A. Maali & M. T. Hamed Mosavian

To cite this article: A. Maali & M. T. Hamed Mosavian (2013) Preparation and Application of
Nanoemulsions in the Last Decade (2000–2010), Journal of Dispersion Science and Technology,
34:1, 92-105, DOI: 10.1080/01932691.2011.648498

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Journal of Dispersion Science and Technology, 34:92–105, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0193-2691 print=1532-2351 online
DOI: 10.1080/01932691.2011.648498

Preparation and Application of Nanoemulsions in the

Last Decade (2000–2010)
A. Maali and M. T. Hamed Mosavian
Chemical Engineering Department, Engineering Faculty, Ferdowsi University of Mashhad,
Mashhad, Iran

GRAPHICAL ABSTRACT

An emulsion is a system containing two immiscible phases: a dispersed phase and a continuous
phase. Components needed to prepare an emulsion are oil, water, surfactant, and energy. The
nature of surfactant determines the type of emulsion (oil-in-water (O/W) or water-in-oil
(W/O)). A nanoemulsion is an emulsion with 20–200 nm droplet size. The required energy to form
a nanoemulsion can be obtained from a mechanical device (high-energy emulsification) or from the
chemical potential of the components (low-energy emulsification). High-energy emulsification
consists of high-pressure homogenization (HPH), ultrasonication, and microfluidization and
low-energy emulsification consists of phase inversion temperature (PIT), phase inversion compo-
sition (PIC), and solvent diffusion. O/W nanoemulsions have been studied more than W/O nanoe-
mulsions and the preparation of nanoemulsions with high-energy emulsification is more reported
than low-energy emulsification. The small droplet size of a nanoemulsion enhances the emulsion
stability; therefore, nanoemulsions have various applications in the industrial field, such as per-
sonal care and cosmetics as well as health care, food, and agrochemicals. Pharmacy and cosmetics
are fields where more direct applications of nanoemulsions are proposed.
Keywords High-pressure homogenization, nanoemulsion, phase inversion composition,
phase inversion temperature, ultrasound

Received 15 November 2011; accepted 1 December 2011.
Address correspondence to M. T. Hamed Mosavian, Chemical
Engineering Department, Engineering Faculty, Ferdowsi Univer-
sity of Mashhad, Mashhad, Iran. E-mail: hmosavian@gmail.com
or mosavian@um.ac.ir
1. INTRODUCTION
An emulsion is a system containing two immiscible
phases, one of which is the dispersed phase as droplets
(internal phase) and the other is the continuous phase
(external phase).[1] There are two types of emulsions:
water-in-oil or inverse emulsion and oil-in-water or direct
emulsion.[2] Emulsions can be categorized into three groups
depending on the emulsion droplet size (EDS):micro

92
 PREPARATION AND APPLICATION OF NANOEMULSIONS
(10–100 nm), mini (nano) (100–1000 nm), and macroemul-
sions (0.5–100 mm).[3,4]
The inherent stability of an emulsion increases as the
droplet size decreases. This is evident from the Stokes-
Einstein equation, which expresses that sedimentation rate
depends on the square of the radius of the droplets.[5]
There are many degrees of freedom in the preparation
of emulsions, such as emulsification process and con-
ditions, the type and amount of surfactants, the location
of surfactant, the presence of electrolytes and co
surfactants, etc.[1]
If only mechanical agitation is used, dispersion of the
dispersed phase in a continuous phase is usually unstable.
This is because, if stirring stops, the two phases are sepa-
rated. To overcome this problem, that is, to make a kineti-
cally stable emulsion, the surfactant or emulsifier is added
to the emulsification system as a third component. The nat-
ure of the surfactant determines the type of the emulsion. If
the surfactant is oil-soluble the resulting emulsion is a
water-in-oil (W=O) emulsion. On the other hand, if the sur-
factant is water-soluble the continuous phase of emulsion is
water and the emulsion formed is an oil-in-water (O=W)
emulsion.[6] Generally, the phase in which the emulsifier
is most soluble is considered as a continuous phase. The
choice of right emulsifier is very important. The desired
stability of emulsion cannot be usually obtained by using
a single surfactant. It is known that a surfactant with a
broad chain length distribution usually makes a more
stable emulsion. Moreover, the emulsion stability can be
improved by utilizing a mixture of surfactant.[1] In this
way, the dispersed phase from coalescing into a macro-
scopic phase is prevented.[7]
Griffin[8,9] based on the stability of the emulsion, intro-
duced the concept of hydrophilic-lipophilic balance (HLB).
The HLB number is a measure of the size and strength of
the two hydrophilic and lipophilic groups in an emulsifier
molecule. Rather than the over-all efficiency of the emulsifier,
this number indicates what kind of an emulsion is produced.
It is better to use a mixture of surfactants with the same
HLB number. The mixed HLB values were calculated by
the following equation:
HLBmix ¼ HLB1 W1 % þ HLB2 W2 % þ . . . ;
where W% is weight percentage of each surfactant.[10] HLB
number affects spontaneous emulsification and EDS. For
formation of O=W emulsions Surfactants with HLB >10
are suitable.[11]
Since the 1980s, attention has been focused on emul-
sions with nanometric droplet size, which are referred to
as nanoemulsions, mini-emulsions, fine-disperse emulsions,
homogeneous emulsions, submicron emulsions, or unstable
microemulsions.[10] Nanoemulsions can be divided in to
two groups based on droplet size namely transparent or
93
translucent (50–200 nm) and milky (up to 500 nm).[12] As
nanoemulsions have a small size, they often possess long-
term physical stability and their properties are superior to
the conventional emulsions.[10] Nanoemulsions can be pro-
duced at moderate surfactant concentration (in the range
of 4 to 8 wt%) while for formation of microemulsion with
high concentration of surfactants is needed (usually inthe
range 10–30 wt%).[12] One can produce nanoemulsions by
two methods: high-energy and low-energy emulsification
methods.[10]
In this review, we will discuss four topics: Section 2 is
dedicated to fundamental principles of emulsification pro-
cess and the role of surfactants. In Section 3, we consider
production of nanoemulsions using high-energy emulsifi-
cation which consists of HPH, microfluidization, and
ultrasonication. In Section 4, production of nanoemulsions
using low-energy emulsification, which consists of PIT, PIC,
and solvent diffusion is considered. Application of nanoe-
mulsions and some examples of it are given in Section 5.
In this article, the methods of preparation of nanoemul-
sions, the pattern of usage of each method and various
application of nanoemulsions in the past decade (2000–
2010) is studied.
2. FUNDAMENTAL PRINCIPLES OF EMULSIFICATION
PROCESS AND THE ROLE OF SURFACTANTS
Components needed to prepare an emulsion are oil,
water, surfactant, and energy. The total free energy of
formation of an emulsion (DG) can be obtained using the
following equation:
DG ¼ DAc þ TDS;
Where DA is the increase in interfacial area, c is the inter-
facial tension, T is the temperature of process, and DS is the
amount of change in entropy. The value of DG is positive
because the value of entropy of dispersion TDS, which is
positive, is greater than absolute value of consumed energy
(jDAcj). The positive DG leads for nonspontaneous
emulsion formation and hence energy is required to have
produced the droplets. The formation of large droplet
emulsions (macroemulsions) is easy. Therefore, to produce
macroemulsions, high speed stirrers such as the Ultraturrax
or Silverson Mixer is adequate. In contrast to the formation
of small drops (nanoemulsions) is difficult and requires a
large amount of energy.
During emulsification various processes occur, among
which disruption of droplets, adsorption of surfactants
and droplet collision are some examples. Each of the above
processes occurs numerous times during emulsification and
the time of each process is about a microsecond. This high-
lights the dynamic nature of the emulsification process and
events that occur in a microsecond range are very important.
94 A. MAALI AND M. T. HAMAD MOSAVIAN
Surfactant reduces the interfacial tension (c) and, conse-
quently, the droplet size is reduced. Some mixtures of surfac-
tants lead to lower interfacial tension than when either is
used individually. In addition, surfactants have an impor-
tant effect on the deformation and disruption of droplets
and prevent coalescence during emulsification. Surfactants
with HLB > 7 form O=W emulsions and HLB < 7 form
W=O emulsions. The disperse phase volume fraction (U) is
the most important factor in emulsification. Increasing the
disperse phase volume fraction causes an increase in droplet
collision and, hence, coalescence during emulsification. In
addition, increasing U, leads to increase of the viscosity of
the emulsion, which could change the flow from being
turbulent to being laminar. The increase in U induces turbu-
lence depression in turbulent flow resulting in larger dro-
plets. In addition, if polymers are added to the system,
turbulence depression tends to remove the small eddies
and, hence, larger droplets will be formed.[13]
The required energy to form nanoemulsions can be
obtained from mechanical device or from the chemical
potential of the components. Preparation of nanoemul-
sions can be categorized in two groups: i) dispersion or
high-energy emulsification methods and ii) condensation
or low-energy emulsification methods.[14]
3. HIGH-ENERGY EMULSIFICATION
High-energy methods use intense mechanical forces to
disrupt droplets into smaller droplets, and typically involve
the use of mechanical devices.[15,16] The methods in this cate-
gory have a drawback, which is that they need high energy
to prepare nanoemulsions and, therefore, they are unfavor-
able for many industrial applications.[13] The formation of
nanoemulsion droplets directly depends on controllable for-
mulation parameters such as the amount of energy, the
amount of surfactant and the nature of the components.[17]
High-energy methods can be categorized in three
groups: i) HPH,[14,15] ii) microfluidization,[18,19] iii)
ultrasonication.[14,15]
HPH and microfluidization can be used at both laboratory
and industrial scale while ultrasonication is primarily used at
laboratory scale. Although high-energy methods are effective
in reducing droplet size, they are undesirable for labile drugs
and macromolecules, such as proteins and nucleic acids, for
which low-energy emulsification methods are used.[20]
3.1. HPH
Conventional HPH works in 50–100 Mpa pressure.
Although with new equipment pressure of 350 Mpa is reach-
able, O=W nanoemulsion with methylcellulose as a surf-
actant can stable with the pressure less than 150 Mpa.[14]
In,[21] the authors prepared nanoemulsions by a simple
homogenizer to avoid high-pressure condition. They
prepared nanoemulsion containing Itraconazole by simple,
conventional homogenization using Ultra-Turrax homoge-
nizer, at a speed of 24000 rpm.
In a standard procedure, materials are passed among the
narrow gap of homogenizer in high pressure (50–200 Mpa).
This high pressure causes a strong disruptive force such as
shearing, collision, and cavitation. Intensive turbulency
and hydraulic shear cause coarse emulsion change to
nanoemulsion.[22] The droplet size depends on the number
of cycles, the pressure, and temperature of the system. The
more the number of cycles and the pressure, the smaller the
size of droplets produced[22,23] (Figures 1 and 2).
In addition, this size also depends on emulsion com-
position (e.g., organic and aqueous phase and surfactant),
emulsifier’s characteristic (e.g., adsorption kinetic, interfa-
cial tension depression, and stabilizing properties), and
physicochemical condition of different phases (e.g., viscosity
and interfacial tension).[23] HPH can be processed in high
temperature (hot HPH technique) or in low temperature
(cold HPH technique), which then later is used for proces-
sing temperature labile drugs.[24] Comparing to other proce-
dures, HPH has many advantages such as easy scale up,
avoidance of organic solvents, and small process time.
HPH is widely used in many industrials specially in
pharmacy and cosmetic.[25] The pattern of usage of HPH
is illustrated in Figure 3.[19,23,26–81]
3.2. Microfluidizer
Oil and aqueous phase are mixed together and enter the
homogenizer to produce coarse emulsion. This coarse emul-
sion enters the microfluidizer to produce stable nanoemul-
sions. In the microfluidizer, a high-pressure pump is used.
This pump, which works in high pressure up to 2000 psi,
forces the produced emulsion to pass through the interac-
tion chamber, which has some microchannels. Therefore,
the emulsion’s droplet will be very small.[20,22] The diameter
of nanoemulsions’ droplets depends on the pressure of the
operation and the number of microchannels in interaction
chamber. As illustrated in Figures 3 and 4, the more the
pressure and the number of cycles, the smaller the size of
FIG. 1. Effect of homogenization pressure on droplet size of nano-
emulsion: HPH (~); microfluidization (&).[19]
 PREPARATION AND APPLICATION OF NANOEMULSIONS 95

FIG. 2. Effect of homogenization cycles on droplet size of nanoemul-

sion: HPH (~); microfluidization (&).[19]

nanoemulsions’ droplets. The produced nanoemulsion can

be filtered through a 0.2 mm filter under nitrogen to remove
FIG. 4. Effect of emulsification on temperature of emulsions: micro-
large droplets and have a uniform nanoemulsion.[20] fluidization at one cycle – with cooling (~), and without cooling (&).[82]
Generally, inertial forces in turbulent flow along with
cavitation cause droplet disruptions in the microfluidizer.
Due to high input energy disruption of droplets is high. As
The advantage of microfluidizer is that the distribution of
long as the disruption is successful, new droplets are pro-
droplets in nanoemulsion is narrower than that of other
duced. However, new droplets are thermodynamically
emulsifying devices. However, microfluidization is unfavor-
unstable and tend to re-coalescence. If the re-coalescence is
able in specific cases, such as high pressure and longer emul-
higher than the disruption, the EDS increase. Increasing
sification time, since it leads to re-coalescence of emulsion
the energy over the optimum limit causes over-processing
droplets and an increase in EDS. The temperature of nano-
because, in high flow rates, the average time of residence of
emulsions at the exit of the interaction chamber is linearly
emulsion decreases. Therefore, the stability of the new inter-
dependent on pressure and emulsification time. Higher tem-
face is low due to slow adsorption of the emulsifier. This
perature leads to a decrease in viscosity and interfacial ten-
results in the re-coalescence being decreased with residence
sion and facilitates droplet breakup. The most important
time and the EDS being increased. Fast stabilizing new inter-
problem in high-energy emulsification is the increase in tem-
face through choosing proper and sufficient surfactant mole-
perature which leads to re-coalescence of emulsion droplets
cules can be used to prevent droplet re-coalescence after
and increase in EDS. To alleviate this and to have small dro-
disruption of large droplets. This prevention can be done
plets, a cooling jacket is used. The effect of the cooling jacket
using hydro-dynamical effect, for example, increasing the
on temperature of emulsification is shown in Figure 4.[82]
viscosity of continuous phases.[82] The pattern of usage of
The input energy during microfluidization can be
microfluidizer is illustrated in Figure 5.[18,19,29,82–101]
improved by increasing the operation pressure or the time
of emulsification. This is done by repeating the operation in 3.3. Ultrasound
two or more cycles. The final EDS is the result of competition Ultrasound is very effective in decreasing the droplet size;
between disruption of droplets and re-coalescence of them. however, it is appropriate for small batches. The process

FIG. 3. The pattern of usage of HPH in the last decade. (Figure avail- FIG. 5. The pattern of usage of microfluidizerin the last decade.
able in color online.) (Figure available in color online.)
96 A. MAALI AND M. T. HAMAD MOSAVIAN
FIG. 6. Effect of 3 different ultrasonicationresidence time on particle
size.[89]
efficiency depends heavily on ultrasonication time in
different amplitudes.[14] In this equipment, ultrasound
energy large droplets disrupt to smaller ones.[22] In ultraso-
nication, the temperature is linear function of the time.
Ultrasonication has a similar behavior to microfludization
at a high temperature. The ultrasonication time has an impor-
tant effect in droplet size. As the time increases, the amount of
energy increases as well, leading to more droplets to be dis-
rupted and, therefore, to a decrease in EDS. Increasing the
residence time over the optimum limit has no effect on
EDS, but wastes energy (Figure 6). Therefore, one should
not expect that droplet disruption increases and droplet sizes
decreases when the amount of energy increases. The input
energy should maintain at a level at which the EDS is the low-
est. Usually there is no over-processing in ultrasound emulsi-
fication. This is because residence time of emulsion in
emulsification region, which is equivalent to sonication time,
is high in equipment, while the residence time in interaction
chamber in the microfludizer is about millisecond.[82]
Despite the simplicity of the ultrasonication, it results in a
less than optimal heterogeneous distribution of nano-
droplet size. Moreover the ingredients would suffer from
the damage due to high-energy output.[22] The distribution
of the size of droplets depends on coarse emulsion input
to ultrasound. If the coarse emulsion entered to sonication
chamber has larger EDS and vaster distribution, the
produced nanoemulsion will have droplets with larger
FIG. 7. The pattern of usage of ultrasound in the last decade. (Figure
available in color online.)
diameter.[82] The pattern of usage of ultrasound is illustrated
in Figure 7.[15,82,89,102–145]
4. LOW-ENERGY EMULSIFICATION
Nanoemulsion, in addition to high-energy methods, can
be obtained by low-energy methods. Such methods only
require gentle mixing and involve the physicochemical
properties of the surfactants and co-surfactants.[17,146–148]
To form a nanoemulsion, this method involves only a low
amount of energy. For the mixing process, the magnetic stir-
ring must be fast enough. But stirring did not break the dro-
plets and the yield of emulsification and droplet size did not
depend on the rotation rate of the magnetic stir bar.[149]
These methods have been extensively attractive in both
theoretical studies and practical applications,[150] because
of their low equipment cost.[10] Low-energy methods are
based on the spontaneous formation of emulsions under
specific system compositions or environmental conditions
which are results of change in interfacial properties.[151]
These changes can be achieved through different ways,
such as keeping the composition fixed while the tempera-
ture is changed (PIT) and the temperature is kept constant
and the composition is changed (PIC).[147,152]
Low-energy emulsification to form nanoemulsion can be
categorized in three groups: i) PIT,[12,153] ii) PIC,[146,147]
iii) solvent diffusion.[14,154]
4.1. PIT
PIT method which was introduced by Shinoda,.[155,156]is
an emulsification technique with low energy, which provide
the formation of nanoemulsions without the use of high
shear forces.[157] Advantages like being low cost make the
PIT method achieves more attention in recent years. The
PIT concept is based on one type of phase inversion in
emulsions (transitional inversion) induced by changing
temperature which affect the HLB of the system (vertical
arrow in Figure 8).[13]
FIG. 8. Phase inversion of emulsification.[146] (Figure available in
color online.)
 PREPARATION AND APPLICATION OF NANOEMULSIONS
When the affinity of the surfactant for the water phase
equilibrates its affinity for the oil phase Transitional phase
inversion occurs. The variation in the affinity or HLB of the
surfactant can be performed by changing temperature.[6] It
is based on the changes in affinity of polyoxyethylene-type
nonionic surfactants with temperature. At low temperature,
the surfactant monolayer has a large positive spontaneous
curvature (more convex) and becomes hydrophilic and
hence O=W emulsion is produced. At high temperatures,
because of dehydration of hydrophilic tailin a nonionic sur-
factant, the spontaneous curvature becomes negative (more
concave) and the surfactant becomes lipophilic and, there-
fore, W=O emulsion is produced. At intermediate tempera-
tures (the HLB temperature), the spontaneous curvature
becomes close to zero (neither convex nor concave) and a
microemulsion (bicontinuous, D) or lamellar liquid crystal-
line phase region appears. The interfacial tension is very low
at the HLB temperature, and hence very small-sized emul-
sions are produced.[14,148] It is possible that these nano-
dropscoalesce to form a macroemulsion with drops in the
1–10 mm range and beyond. If there exists a large amount
of Surfactant and=or if some liquid crystal structure are
formed near HLB of 0, then the nanoemulsion droplet does
not coalesce immediately and while the HLB is moved away
from the unstable region, the droplet size remains in the
50–100 nm range.[158] Therefore, although emulsification is
favored at the HLB temperature, the emulsions are very
unstable.[14] This means that a quenching process needs to
be undertaken to produce stable and fine nanoemulsions,
and the final nanoemulsions need to be stored at a tempera-
ture far from the PIT point.[148] If the emulsion prepared at
a temperature near the PIT is rapidly cooled or heated,
kinetically stable emulsions with small droplet size and
narrow size distribution can be produced. if the emulsion
is rapidly cooled, the W=O emulsion invert to an O=W
emulsion, and if the emulsion is rapidly heated, the O=W
emulsion invert to an W=O emulsion occurs.[146,159] If the
cooling or heating process is not fast, coarse emulsions
are formed.[14]
The mechanism of formation of the W=O nanoemulsion
from a D microemulsion is shown schematically in Figure 9.
In Figure 9a, the temperature is below the PIT, therefore,
FIG. 9. The mechanism of phase inversion temperature for producing
of W=Onanoemulsions (adapted with permission Anton and Van-
damme.[151]) (a) temperature is below the PIT, (b) temperature is
increased, (c) temperature is at the PIT, (d) temperature is above the PIT.
97
the nonionic surfactant are hydrophilic, and hence O=W
macroemulsion is produced. If temperature increases, the
surfactant gradually becomes lipophilic and is solubilized
by the oily phase (Figures 9b). In Figure 9c, the tempera-
ture increases and reaches PIT, therefore, a bicontinuous
microemulsions is formed. If temperature is brought above
the PIT, the O=W emulsion inverts to W=O emulsion, and
because of minimum interfacial tension in PIT, the droplet
of emulsion is small and W=O nanoemulsion is produced
(Figure 9d).[151] The difference in droplet size, before and
after inversion can be clearly be seen (Figure 10). The crude
emulsions (before inversion) are ‘‘milky’’ and opaque
meaning that large droplets. However, the nanoemulsions
(after inversion) are almost transparent.[157]
The characterization tools for determination of the PIT
point include: conductivity,[153,160,161] viscosity,[157]dynamic
light scattering,[12,162] cryo-TEM,[157] light microscopy,[157]
turbidity,[153] optical microscopy.[153]
By monitoring the changes of the conductivity and tur-
bidity with temperatures in emulsion system with nonionic
surfactant for preparation W=O nanoemulsion (Figure 11),
there will be a sudden drop in the conductivity curve and
sudden increase in turbidity curve (inverse relation), this is
because, with increasing temperature, O=W emulsion
change to an intermediate phase and then change to W=O
emulsion. For preparation of O=W nanoemulsions, the
result of this experiment is reversed. An average temperature
between the temperatures at the maximum and minimum
FIG. 10. Nanoemulsion before inversion (right) and after inversion
(left).[157] (Figure available in color online.)
98 A. MAALI AND M. T. HAMAD MOSAVIAN
FIG. 11. The relation between turbidity and conductivity versus
temperature.[153]
conductivity and turbidity value consider as PIT
point.[12,153] The pattern of usage of PIT is illustrated in
Figure 12.[12,148,151,153,157,160,162–178]
4.2. PIC
a. In this technique a transition in the spontaneous curva-
ture obtained by changing the water volume fraction,
Instead of the temperature. This transition is referred to
as catastrophic phase inversion (horizontal arrow in
Figure 8).[146,148] For PIC, the emulsification method
continuous phase components are slowly added over
the dispersed phase components. As a result, in some
place along the emulsification path, a phase inversion
occurs in which bicontinuous phase appears.[179]
Although nanoemulsification is a spontaneous process,
the driving forces are small and reaching equilibrium sys-
tem needs long time.[180] Emulsions are prepared using
FIG. 12. The pattern of usage of PIT in the last decade. (Figure avail-
able in color online.)
PIC methods as illustrated in Figure 13 in five steps: i)
first surfactant and co-surfactant (Smix) are mixed, then
oil and Smix mixed together to form oil phase; ii) water is
added drop wise to the surfactant and oil mixture (the
addition rate is very important and should be adjusted
to ensure it is slow enough such that the bicontinuous
D phase or oil-in water phase is formed; if this rate is very
slow, the droplet size increases due to emulsion destabili-
zation. Water droplets are produced in a continuous oil
phase by adding water into oil (W=O microemulsion);
iii) as the water volume fraction increased, the droplets
start to become bigger; iv) an increase in water volume
fraction causes droplets to merge together and bicontin-
uous or lamellar structures to be formed; at this time
emulsion inversion point is reached, which surfactant
curvature changes and minimal interfacial tensions are
achieved and, therefore, the emulsions with small droplet
is formed; the emulsion inversion point can be deter-
mined by conductivity measurement. If in the inversion
zone, W=O emulsion converts to O=W emulsion
(Figure 14), a sharp increase in conductivity will be
observed; in contrast if O=W emulsion converts to W=
O emulsion, a sharp decrease in conductivity will be
observed; v) further increasing the water content, the
emulsion inversion point is passed and the bicontinues
structure decompose into smaller oil droplets; from this
stage increasing the water does not change the droplet
size. For a complete solubilization of the oil near the
emulsion inversion point, a high surfactant concentration
is required.[146,148,181,182]
The PIC emulsification method for preparation of
nanoemulsions enjoys many advantages, such as, low
preparation cost, absence of organic solvents, good pro-
duction feasibility, long stability, and thermodynamic stab-
ility.[183] The pattern of usage of PIC is illustrated in
Figure 15.[10,15,16,146,147,150,152,179,181–214]
4.3. Solvent Diffusion
Solvent diffusion emulsification technique depends on
the many parameters, such as, interfacial tension, interfacial
FIG. 13. The mechanism of phase inversion composition for produc-
ing of O=W nanoemulsion: water (&), and oil (&). (a) oil phase, as the water
volume increases: (b) forming water droplets, (c) the droplets become lar-
ger, (d) forming bicontinuous structures, (e) forming O=W nanoemulsion.
 PREPARATION AND APPLICATION OF NANOEMULSIONS
FIG. 14. The relation between electrical conductivity versus water
weight fraction.[150]
and bulk viscosity, phase transition region and surfactant
concentration and structure.[154] In theory, the solvent
diffusion nanoemulsification process can provide the same
amount of O=W as W=O nanoemulsions, but most studies
concern O=W generation. This technique is based on the
rapid diffusion of an organic solvent (e.g., acetone, etha-
nol...) from the oil phase to the aqueous phase. Evolution
of the system is improved by diffusion of a solute into the
phase in which it has greater solubility.[17]
Nanoemulsions can be formed in the absence of surfac-
tants and strong shearing, known as ‘‘diffusion and strand-
ing’’ or the ‘‘Ouzo effect’’.[14,215] In Ouzo effect, oil droplets
are produced and their diameter is a function of the ratio of
excess oil to water-soluble solvent. In some studies related
to this method, surfactants have been added to the system.[14]
The method to obtain nanoemulsion with surfactant has
three steps: i) preparation of the organic phase and aqueous
phase; organic phase consists of oil and a lipophilic surfactant
in organic (water–miscible) solvent and aqueous phase con-
sists of water and hydrophilic surfactant; ii) under magnetic
stirring, the organic phase is injected in the aqueous phase;
by diffusion of the organic solvent in the aqueous phase, oil
FIG. 15. The pattern of usage of PIC in the last decade. (Figure avail-
able in color online.)
99
FIG. 16. The pattern of usage of solvent diffusion in the last decade.
(Figure available in color online.)
nanodroplets instantaneously formed; for reaching the equi-
librium system, stirring should maintain for about 30 min-
utes; iii) by evaporation under reduced pressure for 45
minutes, organic solvent is removed from the system and oil
droplets dispersed in an aqueous phase.[154]
The oil viscosity, the HLB of surfactant and the water
solubility of the organic solvent are important parameters
in determining the quality of the nanoemulsions obtained
by solvent diffusion emulsification process. Based on the
nature of the oil used, there is a large difference in the aver-
age size of droplets. The most viscous oil, gave drops with
the smaller size. However, to obtain emulsions with small
drops size the high viscosity of oil is not a sufficient con-
dition.[154] Some limitations of solvent diffusion method
are as follows: i) low amount of oil which dispersed in
aqueous phase (typically 1%); ii) selection of appropriate
organic solvent that is soluble in water in all proportions;
iii) removal of solvent.[14]
The pattern of usage of solvent diffusion is illustrated in
Figure 16.[149,154,216–223]
5. APPLICATION OF NANOEMULSION
Nanoemulsions have various applications in the indus-
trial field, such as personal care and cosmetics as well as
health care, food, and agrochemicals. Nanoemulsions are
appealing principally due to the following reasons:
i. no creaming or sedimentation occurs on storage of
nanoemulsion because of very small droplet size that
reduces the gravity force and Brownian motion.
ii. no separation occurs in nanoemulsion because the
small droplet size prevents any flocculation.
iii. ncomparison to microemulsion, preparation of
nanoemulsion need low concentration of surfactant.
(5–10%).[13,154]
As illustrated in Figure 17, the pharmaceutical and cos-
metic application of nanoemulsion.[27,30,37–41,43–48,51,53–62,
64–73,75,77,78,81,86,93,95,97–109,111–118,122–127,129–137,139,140,142,145,
164–167,169–172,177,178,182–186,188,189,191,192,194–206,208–211,213,216–
224]
in comparison to food industry.[23,26,31,35,36,42,74,76,79,80,
87,88,94,121,225]
and other industry.[84,110,144,176,181] is substantial.
100 A. MAALI AND M. T. HAMAD MOSAVIAN
FIG. 17. Application of nanoemulsions in the last decade. (Figure
available in color online.)
Nanoemulsions are used in the pharmaceutical field as
drug delivery systems. This is due to the following reasons:
i. Nanoemulsions can be formulated in variety of formu-
lations such as foams, creams, liquids and sprays.
ii. Nanoemulsions have a much higher surface area than
conventional emulsion and therefore it is suitable or
delivery of active ingredients through the skin.
iii. Nanoemulsion deposit uniformly on skin and has high
penetration, due to the small size of the droplet and
low interfacial tension.
iv. The transparent and fluidity nature(at reasonable oil
concentrations) of the system, may give nanoemulsion
a pleasant aesthetic character and skin feel.
v. Nanoemulsion can be applied for delivery of fragrant,
which may be suitable in cosmetic and perfume
products.
vi. Nanoemulsions may be applied as a substitute for
liposomes and vesicles which are much less stable
vii. Nanoemulsions constitutes the first step in producing
nanocapsules(encapsulated drug nanoparticles) and nano-
spheres (drug nanoparticles in polymer matrix).[13,154]
The following are some examples of pharmaceutical appli-
cation of nanoemulsion: cancer and tumor therapy,[111–
113,131,133,204]
anti-inflammatory,[97] malaria trea-
[103,224]
tment, nonviral vectors for plasmid DNA
delivery,[123] treatment of coronary artery disease,[132] ocu-
lar drug delivery.[137] Celecoxib nanoemulsion for arthritis
and osteoarthritis treatment,[183,199–202] Carbamazepine
nanoemulsion for anticonvulsant drug,[189] Ramipril
(antihypertensive drug) Nanoemulsion,[182,194–196] and
Calixarene-entrapped nanoemulsion for uranium skin
decontamination.[208,209]
Creams and lotions formulated with Buriti oil (Mauritia-
flexuosa),[177,178] palm oilesters-in-water, and virgin coconut
oil-in-water,[184] are examples of nanocosmeceuticals. With
respect to agrochemical applications.[181] O=W nanoemul-
sions are produced as solubilizing water-insoluble,
b-cypermethrin. The system consists of water, polyoxy
ethylene nonionic surfactant and methyl decanoate which
serves as an oil phase. In this article spray formulations of
b-cypermethrin is achieved that in comparison to conven-
tional O=W microemulsion pesticide has more economical
and environmental friendly.
In Fallah and Falamaki,[110] an application of nanoemul-
sion in catalyst engineering is considered. In this article a novel
methods for production of rod shaped 2Li2O=MgO catalyst
nanoparticles on the internal surface of porous carriers (a

Al2O3) for the Oxidative Coupling of methane reaction is dis-
closed. The required nanoemulsion for this technique is W=O
nanoemulsion which is produced by ultrasonic probe.
In Choi and Kang,[84] a new method to prepare a nano-
emulsion system containing much smaller dye particles of
nanosize in the range of 110 to 130 nm has been investi-
gated. Six nano-disperse dyes were prepared using O=W
nanoemulsions, which were produced by the microfluidizer.
There are potential applications of nanoemulsions in
food technology, but there isn’t much specific application
in recent articles. As illustrated in Figure 17 application
of nanoemulsion in food technology is limited to recent
years. For example, Yuan et al.[79,80] investigated the pro-
duction of b-carotene (an important dietary antioxidant
and precursor of vitamin A) nanoemulsion. In these articles
b-carotene is considered as the dispersed phase.
As discussed above, pharmacy and cosmetic are fields
where more direct applications of nanoemulsions are pro-
posed. In pharmacy, most of the drugs are lipophilic and such
drugs are preferably solubilized in O=W nanoemulsions.[187]
Therefore, as illustrated in Figure 18, the production of
O=W nanoemulsions (in high-energynanoemulsifica-
tion)[15,18,19,23,26–28,30–32,35–39,41–45,47,48,51,53,54,56–71,73,76,79,80,
82–96,102–106,109,112,113,118–120,122,124,125,127,138,140,142,143,224]
and
low-energy nanoemulsification is[10,12,15,16,146,148,150,152–
154,162,163,165–179,181–186,188,190,191,193–195,197,198,202,203,205,208–214,
216,222]
) very much than W=O nanoemulsion (in high-energy
nanoemulsification[110,116,145] and low-energy nanoemulsifi-
cation.[160,164,204,226])
With respect to Figure 19, in spite of requirement high-
energy input, High-pressure homogenization,[27,30,37–41,43–
48,51,53–62,64–73,75,77,78,81]
and ultrasonication[102–109,111–118,
122–127,129–137,139,140,142,145,224]
methods are more attractive
FIG. 18. The pattern of usage of two different methods in nanoemul-
sification and type of nanoemulsion in the last decade. (Figure available in
color online.)
 PREPARATION AND APPLICATION OF NANOEMULSIONS
are proposed. In pharmacy, because of the lipophilic nature
of drugs, production of O=W nanoemulsion is more than
W=O nanoemulsion.
REFERENCES
FIG. 19. The pattern of usageof different methods in nanoemulsifica-
tion in pharmacy and cosmetic fieldsin the last decade. (Figure available in
color online.).
methods in pharmacy and cosmetic field for nanoemulsion
preparation because of low process time in comparison to
other methods such as microfluidization,[86,93,95,97–101]
PIC,[182–186,188,189,191,192,194–206,208–211,213] PIT,[164–167,169–
172,177,178]
and solvent diffusion.[216–223] HPH and ultrasoni-
cation are classified in high-energy methods as discussed
earlier. Therefore, as illustrated in Figure 18, the high-
energy nanoemulsification is more used than low-energy
emulsification.
5. CONCLUSION
The small droplet size of nanoemulsion enhances emul-
sion stability and creaming or sedimentation should not
occur even on prolonged storage, also the small size prevents
flocculation of the droplets as well as their coalescence.
Therefore, the production of nanoemulsion is increasing
every year. For production of nanoemulsions, energy is
needed. Base on the way this required energy is provided,
nanoemulsification can be obtained with two general
methods. i) high-energy emulsification in which mechanical
devise is used and ii) the low-energy method in which chemi-
cal potential of the components is used. In spite of high
cost of high-energy method, this method is used widely in
production of nanoemulsion especially in Pharmacy and
cosmetic fields. This is because the process time is low.
The high-energy methods consist of high-pressure
homogenization, ultrasonication, and microfluidization.
In comparison to HPH and ultrasound, the microfluidizer
is less used because of over processing. The low-energy
emulsification consists of phase inversion temperature,
phase inversion composition and solvent diffusion. Solvent
diffusion is less used in comparison to other low-energy
emulsification method. This is because of some limitation
of this method, such as necessity of existence of an organic
solvent which is soluble in water in all proportions.
Nanoemulsions have been widely used in many industries
such as, personal care and cosmetics as well as health care,
food and agrochemicals. Pharmacy and cosmetic are fields
wherein which more direct applications of nanoemulsions
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